Drug combo may knock down lung cancer

Hatim Husain, MD, examines cancer cells at the UCSD Moores Cancer Center. He is one of a team of researchers that have discovered a weakness in certain cancers, and are going to begin trials, paring different cancers drugs to fight otherwise drug resistant cancers. |
— Howard Lipin

Hatim Husain, MD, examines cancer cells at the UCSD Moores Cancer Center. He is one of a team of researchers that have discovered a weakness in certain cancers, and are going to begin trials, paring different cancers drugs to fight otherwise drug resistant cancers. |
— Howard Lipin

Some drug-resistant cancers of the lung, pancreas and breast might be made vulnerable again by treating them with a medication already approved for another type of cancer, according to a new study led by scientists at UC San Diego.

Researchers at UCSD Moores Cancer Center said they plan to start a clinical trial to test the use of Velcade for lung cancer in about six months. This quick start is possible because the drug is currently on the market, said Dr. Hatim Husain, an author of the study who is designing the clinical trial. For more information about the trial, call (858) 822-5182.

Velcade, or bortezomib, is approved to treat relapsed multiple myeloma. But in lab studies, it also appears to re-sensitize cancer cells that had become resistant to Tarceva, or erlotinib. Tarceva is used to combat non-small cell lung cancer and some pancreatic cancers.

For the upcoming clinical trial, all patients will get the Velcade-Tarceva combo; there will be no placebo, Husain said. Patients will be tested for tumor cells and DNA circulating in the blood, which will indicate how they are responding.

Researchers discovered a previously unknown process that causes lung, breast and pancreatic cancer cells to become drug-resistant. Called cancer stem cells or tumor-initiating cells, they resemble embryonic stem cells in how they multiply and spread throughout the body. It’s not known how widely this discovery applies to other cancers, Cheresh said.

The tumor-initiating cells can be identified by a molecular marker on their surface called CD61, the study found. This molecule is necessary to maintain the cell in the stemlike state, Cheresh said. So the researchers looked for drugs that acted against this target. Velcade both reversed the “stemness” of these cells and restored Tarceva’s effectiveness, as tested in mice grafted with patient tumors.

Velcade, generically called bortezomib, reverses the "stemness" of resistant lung cancer cells, making them less dangerous and more vulnerable to Tarceva, generically called erlotinib.
— UC San Diego School of Medicine

Velcade, generically called bortezomib, reverses the "stemness" of resistant lung cancer cells, making them less dangerous and more vulnerable to Tarceva, generically called erlotinib.
/ UC San Diego School of Medicine

Previous studies had suggested that cancer stem cells employ a general drug resistance mechanism. However, the study found that these cells selectively resist a class of cancer drugs that includes Tarceva. That suggested the clinical trial’s approach, which uses the evolution of drug resistance as a weapon against the cancer.

Timing is important for the therapy to have maximum effect, Cheresh said. It doesn’t make sense to give Velcade before the resistance has developed. And the more the cancer has mutated to resist the therapy, the more effective Velcade will be.

“We’re pushing these cells into a corner,” Cheresh said.

Tarceva’s effect may be part of a stress response to cancer cells that causes them to get stemlike properties, Cheresh said. This could include other cancer drugs. But that doesn’t mean the drugs aren’t useful, because they can temporarily stop the cancer. Moreover, individual responses to the drugs differ.

“Patients may view getting these drugs as being a negative, and I think it’s premature to say that just yet,” Cheresh said. “When the patient responds to the drug, it’s a positive thing. What we now need to do is keep in mind we have a biomarker to determine when the tumor becomes resistant and stemlike, so that we can begin to intervene. We’re also working on a blood test to determine when this conversion happens at the earliest possible stage.”

The researchers have made a significant discovery, said Dr. Fadlo R. Khuri, deputy director of Winship Cancer Institute at Emory University in Atlanta

“This is important work, in that it demonstrates a critical biologic feature of cancer initiating cells, or so called cancer stem cells,” Khuri said by email. “These are the cancer cell population which are resistant to targeted therapy and chemotherapy, and can help repopulate a tumor after treatment.”

Previous studies of the Tarceva/Velcade combination failed to demonstrate substantial benefit for lung cancer patients, Khuri said by email. However, testing in a more well-defined group of patients might uncover “previously unseen activity.”

Husain said the more rationally designed combination therapies are available, the more successful doctors will be in keeping cancer in check.